HEALTHCARE PROFESSIONALS No. 3 in a series providing the latest information Facts About Acute Myeloid Leukemia (AML) Introduction Acute myeloid leukemia (AML) is an aggressive, highly complex malignancy typically diagnosed in older adults. Patients with AML often have multiple comorbidities and may not be candidates for aggressive remission induction chemotherapy, the standard of care since the 1970s. In recent years, high throughput genetic sequencing identifying causal mutations and a better understanding of the biology of the disease have resulted in a wave of newly approved targeted therapies. These discoveries and drug approvals have resulted in better options and better outcomes for patients, particularly those who may be unable to tolerate aggressive chemotherapy. This publication will review the updated AML subtype classifications, detail newly approved therapies, summarize current treatment recommendations, and provide information about the LLS Beat AML® Master Trial, collaborative clinical trial testing novel targeted therapies with the goal of improving outcomes for newly diagnosed patients with AML. Highlights ■ ■ AML is a genetically heterogeneous malignancy Since 2017, better understanding of the molecular typically diagnosed in older adults, with a slight male basis of AML has been leveraged to produce 8 newly predominance. approved therapies for AML: for the treatment of newly diagnosed patients, those with relapsed and refractory ■ disease, and those ineligible for aggressive induction AML was diagnosed in over 21,000 people and resulted in nearly 11,000 deaths in the US in 2019. chemotherapy. The incidence of AML has increased 3.7% per year ■ from 2006 to 2015. Updated National Comprehensive Cancer Network (NCCN) Practice Guidelines should be consulted for ■ recommendations regarding where and when each of A multidisciplinary diagnostic approach, including both karyotype and mutation analysis, is critical these therapies fits into clinical practice. to predict rates of remission, relapse, and overall ■ survival, and to identify patients likely to benefit For any patient with newly diagnosed AML, referral to a from targeted therapies. clinical trial is recommended upon diagnosis. ■ ■ Updated classification of AML is based on clinically The Beat AML® Master Trial sponsored by The relevant disease information rather than morphology. Leukemia & Lymphoma Society is a novel, collaborative Six major subtypes of AML were recognized by the clinical trial designed to facilitate the approval of World Health Organization (WHO) in 2016. new drugs and optimize the treatment for AML by developing individualized treatment approaches. ■ The 2017 European Leukemia Network (ELN) Guidelines are widely used for risk stratification and determining the likelihood of treatment resistance. www.LLS.org • Information Specialist: 800.955.4572 December 2019 FSHP3 AML Facts I page 1 Facts about AML Background and Prevalence A diagnosis is made based on the presence of ≥20% myeloblasts in the marrow or peripheral blood established AML is the most common acute leukemia in adults, with by morphology and flow cytometry.5,6 The 2019 NCCN an estimated 21,450 diagnoses and nearly 11,000 deaths Practice Guidelines [available here] (www.jnccn.org/ 1 in the US in 2019. It is also diagnosed at younger ages, view/journals/jnccn/17/6/article-p721.xml) recommend but older adults comprise the majority of patients – the a multidisciplinary diagnostic approach when AML is median age at diagnosis is 67 years, and 65% of patients are suspected. This approach identifies AML subtypes, stratifies diagnosed at age 65 years and older.2 From 2006 to 2015, pre-treatment risk and guides treatment decisions, and the incidence of AML increased 3.7% per year, likely due includes performing the following tests2: to the aging population. It is more common in males by a 3 1. Bone marrow core biopsy and aspirate analysis ratio of approximately 5:3. (including immunophenotyping by flow cytometry and cytochemistry). AML results from genetic or epigenetic changes in hematopoietic precursor cells, resulting in a clone 2. Cytogenetic analysis: Karyotype with fluorescence in of myeloid precursor cells that proliferates, but can’t situ hybridization is needed for risk stratification and can help to confirm the diagnosis. differentiate. These immature myeloblasts expand in the bone marrow, peripheral blood, and other tissues, with a 3. Mutational analysis: For KIT, FLT3-ITD, FLT3- corresponding reduction in the production of normal red TKD, NPM1, CEBPA, IDH1/IDH2, RUNX1 and blood cells, platelets, and mature granulocytes.2 TP53 should be performed in all patients to inform prognosis and treatment. The great majority of AML cases arise without an apparent While identifying karyotype is critical to predict rates of cause, but known and suspected risk factors for AML (other remission, relapse and overall survival, mutation analysis than advanced age and male gender) include those shown in refines risk stratification and identifies those patients likely Table 1. to benefit from recently approved targeted therapies.7 Table 1. Risk factors for AML Subtype Classification and Risk Stratification Critical for Treatment Decisions Risk Factor Examples Updated classification of AML and related neoplasms by Environmental exposures • Benzene, ionizing radiation, cigarette smoke the WHO in 2016 was based on clinically relevant disease Antecedent hematologic • Myeloproliferative disorders, information rather than only morphology. The 6 major 5 disorders myelodysplastic syndromes (MDS) subtypes are shown in Table 2. • Bloom syndrome, ataxia- In terms of risk stratification by genetics, the 2017 ELN pancytopenia syndrome, Diamond- Guidelines (Table 3) are widely used for determining Blackfan anemia, Fanconi anemia, likelihood of treatment resistance.6,8 Genetic syndromes MIRAGE syndrome, Noonan syndrome, Kostman syndrome, 5 Shwachman-Diamond syndrome, Table 2. AML and related neoplasms Down syndrome4 • AML with recurrent genetic abnormalities • Alkylating agents, topoisomerase Previous cancer therapy inhibitors and radiotherapy (given • AML with myelodysplasia-related changes (therapy-related MDS/AML as myeloablative therapy prior to or t-AML*) autologous hematopoietic stem cell • Therapy-related myeloid neoplasms transplantation)2 • AML, not otherwise specified *May constitute 7% to 15% of patients with AML4 • Myeloid sarcoma Multidisciplinary Diagnostic Approach A person with AML usually presents with symptoms of • Myeloid proliferations related to Down syndrome bone marrow failure: abnormally low levels of platelets, neutrophils, and red blood cells, and the presence of circulating blasts with the resulting complications of fatigue, pallor, weakness, increased infections, and bleeding. December 2019 FSHP3 AML Facts I page 2 Facts about AML Table 3. Risk stratification by genetics6,8 Risk Category Genetic Abnormality • t(8;21)(q22;q22.1); RUNX1-RUNX1T1 • Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow = allelic ratio < 0.5 Favorable • inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 • Biallelic mutated CEBPA • Mutated NPM1 and FLT3-ITDhigh = allelic ratio > 0.5 • t(9;11)(p21.3;q23.3); MLLT3-KMT2A Intermediate • Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow • Cytogenetic abnormalities not classified as favorable or adverse (without adverse-risk genetic lesions) • t(6;9)(p23;q34.1); DEK-NUP214 • Complex karyotype monosomal karyotype • t(v;11q23.3); KMT2A rearranged • Wild-type NPM1 and FLT3-ITDhigh • t(9;22)(q34.1;q11.2); BCR-ABL1 Adverse • Mutated RUNX1 • inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); • Mutated ASXL1 GATA2,MECOM(EVI1) • Mutated TP53 • −5 or del(5q); −7; −17/abn(17p) Treatment and Prognosis Despite the genetic heterogeneity of AML, for decades most patients who were fit enough (generally younger patients) received aggressive induction combination chemotherapy consisting of 7 days of cytarabine and 3 days of anthracycline (“7 + 3” regimen), followed by either cytarabine-based consolidation or allogeneic hematopoietic stem cell transplant (HSCT).9 This regimen results in complete remission in approximately 70% of patients younger than 60 years, and approximately 50% of those 60 years and older.7 Relapse occurs frequently, however, ranging from 30%-35% in younger patients with favorable risk factors to 70%-80% in older patients with adverse risk factors. In 2017, the overall survival (OS) rate at 5 years for patients with AML was 27.4%. Adjusted for age, 5-year OS for those younger than 65 was 39% and just 8.5% for patients 65 to 74 years of age.10 Even with active therapy, the typical median OS in relapsed/refractory (r/r) AML is approximately 6 months.11 Options for patients with AML who are ineligible for aggressive chemotherapy have been limited. Less-intensive treatment approaches have included low dose cytarabine (LDAC), which is associated with poor response rates (<15%) and short median survival.12,13 Hypomethylating agents have also been utilized in these patients, resulting in complete response (CR) plus CR with incomplete blood count recovery (CRi) of 20-40%.12,13 Other such patients receive no chemotherapy but opt for supportive care, including hydroxyurea and transfusion support, instead.12,13 Therapies Approved Since 2017 Recently, better understanding of the molecular basis of AML has been leveraged to produce 8 approved therapies from 2017 to 2019 – either as single agents or in combination with other therapies (Table 4). These approvals have provided